In this proposed research project, heparin is modified so that a) a physiologically active heparin molecule can be transported into the systemic circulation when it is administered orally and b) the bioavailabililty of the orally administerd heparin will reach or be close to that of intravenously administered heparin (i.e. about 100% bioavailable). Results from the work done during the past budget period suggest that a) a heparin complex of heparin triethylamine hydrochloride (TEA) has rendered heparin lipophilic and absorbable from the GI tract, but that b) the extent of absorption is still dependent on the molecular size of heparin molecule. To achieve high percentage of bioavailability, lymphatic transport of heparin complex must be utilized. Lymphatic transport, if can be realized, has two advantages, namely, a) the extent of transport will be independent of molecular size and b) the transport will avoid the first pass hepatic degradation of heparin complex. To realize lymphatic transport of heparin complexes, we propose to synthesize "soft" quaternary ammonium ions structurally similar to that of 2-monoglyceride with four C18 fatty acids, namely stearic (sturated), oleic (unsaturated one double bond (db)), linoleic (unsaturated, 2 db) and linolenic (unsaturated 3db). Animal experiments include the macroscopic gastro-intestinal absorption studies (oral and intravenous administrations) to determine the effectiveness of heparin complexes as orally effective therapeutic agents in terms of half-life, clearance biovailability and bioequivalence to the iv regular heparin, and microscopic investigations of the factors which facilitate their lymphatic transport; of their resistance against hepatic degradation. As a result of the above investigation, the machanism of the transport of a heparin complex from the GI tract to the systemic circulation can be understood, and the extent of its transport can be optimized. Also included in this proposal are the in vitro studies of lipophilicity and stability of complexes. Acute and chronic toxicity of complexes on normal rats will also be investigated.